Title:Analgesic and Anti-Inflammatory Properties of Arylnitroalkenes
Volume: 14
Issue: 1
Author(s): Laura Celano, Yolanda K. Cupertino Da Silva, Nicolás Cataldo, Martín Gabay, Alicia Merlino, Magna S. Alexandre-Moreira, Lidia Moreira Lima, Hugo Cerecetto, Mercedes González and Leonor Thomson
Affiliation:
Keywords:
Antioxidants, prostaglandin H synthase inhibitors, inflammation, anti-inflammatory therapy, analgesia.
Abstract: In a recent work, we described the design and synthesis of arylnitroalkenes, able to scavenge macrophagederived
oxidants, in particular peroxynitrite and peroxynitrite derived radicals. Four compounds emerged as potential
leads, 1,1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene (1), 1,1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene (2), 5-
(2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (3), and 5-(2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (4). In the present work, the
possibility of the preclinical validation of these molecules as anti-inflammatory and analgesic was explored in appropriate
in vivo mouse models. Compounds 1, 2 and 4, administered orally as a single dose (30 µmol kg-1) to the mice showed
anti-inflammatory and analgesic properties similar to classic nonsteroidal anti-inflammatory agents. The pharmacological
effects were consistent with the inhibitory effect observed on prostaglandin endoperoxide H synthase (PGHS). In fact,
both PGHS-1 and PGHS-2 were inhibited by the compounds, with compound 2 being more specific as PGHS-2 inhibitor
with a specificity index superior to 70%. Conversely to classical nonsteroidal anti-inflammatory drugs, compound 2
inhibited peroxidase half reaction of the enzyme (IC50 2.3 µM) while the cyclooxygenase activity of hrPGHS-2 remained
unchanged. In vitro experiments were reinforced by docking and molecular dynamics simulations showing arylnitroalkene
moiety located in the region of the peroxidase active site, competing with the peroxide intermediate. The absence of
toxicity and mutagenicity of the compounds was also demonstrated.
